Therapeutic drugs, local anesthetics and other agents, which are collectively referred to in this specification as "biologically effective agents" or "drugs", are often topically applied when concentrated, localized action is desired at specifically delineated regions of a patient's anatomy. These regions may be open wounds or any otherwise afflicted areas, such as cavities. The need for this type of administration may for example arise in the treatment of incisional wounds following surgery, or of accidental incisions, punctures, scrapes or bruises, or in the treatment of localized infections such as insect stings or bites, poison ivy, poison oak, or other allergic skin reactions, burns and sunburn, skin rashes and roughness such as dermatitis, psoriasis, and broken or cracked skin in general, as well as more serious traumas such as wounds caused by accidents or recesses or cavities caused by the removal of tumors from bones. The substance to be administered may be a therapeutic agent or a preventive agent, such as, for example, an antibiotic, antibacterial, antifungal, or anti-infective, applied either prior to or subsequent to the onset of the condition, or an analgesic or anesthetic applied either as the sole treatment or in conjunction with additional treatment such as surgery or first aid.
Localized administration has certain advantages over systemic administration. One is the avoidance of adverse side effects, such as those which accompany the use of narcotics and other systemic pain-killers. Another is the faster action and the concentration of the agent's activity at the area where it is needed, i.e., the more economical and efficient use of the agent.
Topical or other localized administrations which are the most effective, however, are those in which the effect of the agent once administered is prolonged over a period of time. In post-surgical applications and accidental wounds, for example, the anesthetic or antibiotic effect supplied by the agent is often needed for a longer period than can be achieved by simple bolus administration of a drug. Many localized skin infections and rashes also require prolonged treatment. One manner in which this has been achieved is by the combination of the biologically effective agent with a polymeric binder to form solid particles of microscopic size. Release of the agent to the environment, i.e., the surface of the wound or afflicted area to which the formulation has been applied, varies with the concentration of the agent in the particle, the size and shape of the particle, and the lattice or pore structure of the polymer binder matrix.
The use of bioerodible polymers adds a further variable affecting the rate of release. Bioerodible polymers are polymers which, upon exposure to bodily fluids or membranes with which they come into contact upon administration, degrade into low molecular weight species which are innocuously absorbed into or excreted by the patient's body. When bioerodible polymers are used, release occurs by any combination of one, two, three or more mechanisms, examples of which mechanisms are the diffusion of the agent through the polymer itself, the diffusion of the agent through the pores in the polymer matrix, and the erosion of the polymer.
The particles are generally of a very small size which permits them to be applied by spraying or injection. For these types of application, the particles are dispersed in a suitable carrier or vehicle such as a low viscosity or volatile liquid. The small particle size has its limitations, however, particularly in the degree to which the particle can prolong the release rate. Due to the high surface area of the particles and the short diffusion path of the agent through each particle, the release of agent from particles small enough to be applied by spraying or injection is often faster than desired.
One solution to this problem is to use particles which consist of the biologically effective agent microencapsulated in a highly diffusion-limiting shell. However, it is difficult to exert the needed control over the manufacture of particle walls of this nature, and if they can be made of bioerodible materials, control of the release rate is rapidly lost once the walls begin to erode.
Larger particles with a longer release profile may be used, provided that they can be applied by means other than a spray nozzle or a syringe with a fine needle. Larger particles may thus be applied as a dispersion in a low-viscosity or volatile liquid carrier by direct spreading of the dispersion over or into the afflicted area, such as the skin or a body cavity, using a brush, sponge, swab or other surface applicator. Particles of this size have a greater tendency to migrate through the carrier once they have been applied, however, thereby coalescing or drawing together, particularly in areas with an uneven surface such as furrows, ridges or bumps. Such migration makes it difficult to achieve an evenly distributed activity of the biologically effective agent over the entire area to which the particles have been applied or to keep them localized to the area to be treated.
One approach to this problem is the use of a thermogel as the carrier, as disclosed by Speaker, T. J. , et al., in U.S. Pat. No. 4,917,892, Apr. 17, 1990. The thermogel must be physiologically compatible, and must exist as a fluid at or below room temperature and be convertible to a gel at body temperature. Temperature control is thus important during both preparation and application of the formulation, and at room temperature the dispersion is vulnerable to instability. In addition, premature gel formation will limit the ease of application. Another approach is the incorporation of the particles in a sheet such as a bandage which holds the particles immobile. However, sheets are inappropriate for use in those situations where it is undesirable to leave the sheet behind or where retrieval of the sheet is not possible (e.g., incisional wounds or subcutaneous implants). Sheets are also not very satisfactory for use where the wound to be treated is of a very large or, particularly, irregular shape or has an uneven surface topography, so that it is difficult to cover the wound or difficult to keep it covered with a sheet material. Additionally, sheets, even when erodible, may provide a temporary barrier in the area of a healing wound.
These and other shortcomings and disadvantages of existing systems for controlled-release particulate drug delivery systems are addressed by the present invention.
In EP-A-O 244 188 a controlled release drug delivery system for the periodontal pocket is described. The system comprises microparticles consisting of a drug containing polymer having drug dispersed therein and a fluid suspending medium for the microparticles.
WO-A-92/9226 describes a drug delivery system comprising 1) solid particles comprised of lobeline and a biodegradable polymer and 2) a liquid suspending vehicle.
These and other shortcomings and disadvantages of existing systems for controlled-release particulate drug delivery systems are addressed by the present invention.